In the latest World Health Organization’s (WHO’s) guidelines on drug-resistant tuberculosis (DR-TB) treatment, modifications to the recommended all-oral treatments for multidrug- and rifampicin-resistant (MDR/RR) TB and novel regimens for patients with extensively drug-resistant TB are encouraged under operational research conditions.
TDR, in collaboration with the WHO Global Tuberculosis Programme and technical partners, has developed an operational research package (dubbed ShORRT, Short, all-Oral Regimens for Rifampicin-resistant Tuberculosis) to support the implementation of such drug regimens.
Since its official launch in Hyderabad, India, in November 2019, the ShORRT initiative is now involving and supporting 25 countries worldwide, working alongside WHO Regional and country offices, academia, technical partners such as KNCV Tuberculosis Foundation, the Union and Damien Foundation, and funding agencies such as the United States Agency for International Development (USAID) and The Global Fund to Fight AIDS, Tuberculosis and Malaria.
The ShORRT initiative in the Mekong Region
In the Mekong region, three countries (Cambodia, Vietnam and Lao PDR) are among the pathfinder countries conducting operational research on modified shorter all-oral regimens for MDR/RR-TB patients.
Cambodia is the first country worldwide to have launched such operational research. The study, which involves nine study sites, is investigating the effectiveness and safety of a novel shorter all-oral drug regimen for MDR/RR-TB comprising nine months of bedaquiline, linezolid, levofloxacin, clofazamine, compared with the standard treatment regimen with amikacin. At the end of 2020, 125 patients had been recruited to their study, exceeding the initial target of 50 patients.
In Vietnam, the National TB Control Programme is assessing the effectiveness and safety of an MDR/RR-TB treatment regimen containing bedaquiline, clofazimine, linezolid, levofloxacin and pyrazinamide, lasting for 9 to 11 months. About 60 patients have been enrolled in the study since its inception in August 2020, and recruitment is expected to be completed in February 2021.
The ShORRT Study in Lao PDR
Despite significant progress in TB control over the past two decades, TB remains a public health threat in Lao PDR. Estimated TB incidence and mortality are declining steadily but remain high compared with other countries in the region. While 11,000 people
were estimated to have developed TB in 2019, only about 7,000 TB cases were notified, which means that nearly half of the people with TB are still “missing”. The first anti-TB drug-resistance survey in 2016-2017 showed that 1.2% of new
TB cases and 4.1% of previously treated cases had MDR/RR-TB. While the country has experienced fast economic growth and declining poverty in recent years, social disparity and inequitable access to health services contribute to fuelling the TB epidemic.
A recent nationally representative survey found that 63% of TB patients and their families experience costs deemed catastrophic due to their disease.
During 2020, the National Tuberculosis Centre (NTC) adapted the ShORRT research package and developed their study which aims to evaluate the effectiveness and safety of two modified Bedaquiline-containing regimens: a drug regimen comprised of 2 months
of linezolid, 6 months of bedaquiline, and 9 months of levofloxacin, clofazamine and pyrazinamide for patients with TB sensitive to fluoroquinolones; while patients with TB resistant to fluoroquinolones will receive 6 months of bedaquiline, pretomanid
and linezolid (BPaL regimen) as shown in table below:
In addition, the study also aims to assess the impact of these novel drug regimens on the health-related quality of life of patients.
The study will be conducted at all three sites dedicated to the programmatic management of drug-resistant TB in Lao PDR: Sethathirath Hospital, Luang Prabang and Khammuane provincial hospitals. Two additional sites are planned to be opened in mid-2021 in Savannakhet and Champassack provincial hospitals.
“We believe the move towards shorter all-oral regimen is a key step in the programmatic management of drug-resistant TB in Lao PDR,” says Dr Phonenaly Chittamany, Director of National TB Center, Ministry of Health, Vientiane, Lao PDR. “Not only is this new treatment regimen expected to provide better treatment outcomes with fewer failures, relapses, or deaths, but also to improve the quality of life of our patients with less toxicity and adverse events. This will also encourage treatment adherence since it is of shorter duration, with the possibility of community- or home-based DOT and ambulatory care rather than hospitalization to get the injections. And lastly, this will allow the patients to stay closer to their family so that they don't feel homesick.”
About 50 patients will be enrolled in the group receiving the all-oral shorter regimen between January and December 2021.
The comparator group will include patients receiving the standardized shorter regimen with injectables and the all-oral regimen with Bedaquiline.
For patients receiving the standardized shorter regimen with injectables, data are being collected retrospectively since January 2020, and prospectively from January to December 2021. For patients receiving the standard of care with Bedaquiline, data will be collected prospectively for the same period.
Approximately 20 patients will be selected for the quality of life assessment (ten patients in each cohort) across the three study sites.
Despite the challenges posed by the current COVID-19 pandemic, the study has been swiftly established during 2020 through a mix of virtual sessions with the Lao TB programme and WHO regional and TDR teams and on-site activities. These include the readiness assessment of the laboratory network and of the study sites, the customization and piloting of the generic ShORRT data collection platform using the REDCap software, as well as training of data collectors and stakeholders on the study procedures. The first patient started the ShORRT regimen in Luang Prabang in February 2021.
Besides NTC/NRL teams are conducting participatory workshops with provincial and district level physicians to build capacity on decentralized treatment and care for DR-TB patients using all-oral regimens (8-12 February 2021 in Luang Prabang, and 8-12 March 2021 in Khammouane).
It is reasonable to assume that individuals treated for MDR/RR-TB with all-oral shorter regimens would experience better quality of life compared with patients on a standard (either short or long) MDR/RR-TBregimen, through two primary mechanisms. First, an injectable-free treatment itself can potentially improve treatment adherence of patients and facilitate the implementation of community-based models of care. This in turn would reduce direct costs incurred by the patients associated with traveling to the health facility for daily injections (such as transportation, food and accommodation costs), and/or the opportunity costs associated with lost productivity and income due to hospitalization. Second, injectable-free treatment regimens that potentially reduce the occurrence of adverse reactions would likely improve adherence to treatment. It is therefore likely that less quality-adjusted life-year (QALY) would be lost and the overall health-related quality of life of patients would improve. These hypotheses need to be corroborated by further evidence to inform national and international policy, and operational research from pathfinder countries such as Lao PDR, Cambodia and Vietnam will be key in this process.
For more information, please contact Dr Corinne Merle
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